Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• ALK gene rearrangements occur in 3%-5% of non-small cell lung cancer (NSCLC) patients.
• Sequential use of ALK-tyrosine kinase inhibitors (TKIs) has led to the emergence of resistance mutations.
• Compound mutations, like I1171N+F1174I, confer resistance to all approved ALK-TKIs.

Purpose of the Study:

• To investigate the efficacy of gilteritinib against ALK-TKI resistant NSCLC, including specific compound mutations.
• To evaluate gilteritinib's activity in preclinical models of resistant ALK-mutant and NTRK-rearranged cancers.

Main Methods:

• In vitro and in vivo studies were conducted to assess gilteritinib's inhibitory effects.
• Preclinical models expressing specific ALK compound mutations (I1171N+F1174I) and NTRK fusions were utilized.
• Tumor response to gilteritinib was compared with existing ALK-TKIs like alectinib and lorlatinib.

Main Results:

• Gilteritinib demonstrated inhibitory effects on ALK-TKI-resistant single and I1171N compound mutants in vitro and in vivo.
• EML4-ALK I1171N+F1174I mutant tumors, initially resistant to alectinib or lorlatinib, showed significant shrinkage after switching to gilteritinib.
• Gilteritinib exhibited efficacy against entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive cancers.

Conclusions:

• Gilteritinib is effective against various ALK-TKI resistance mechanisms, including challenging compound mutations.
• Gilteritinib represents a potential therapeutic option for patients with resistant ALK-mutant NSCLC and NTRK-rearranged tumors.
• The study highlights gilteritinib's broad-spectrum activity beyond ALK inhibition, extending to NTRK and ROS1 alterations.